DESCRIPTION (applicant's abstract): More than 23 million Americans suffer from clinically significant anxiety and depressive disorders, some 20 million Americans abuse illicit drugs and over 7 percent of the population are dependent on or abuse alcohol. Stress appears to have exacerbating effects on these psychological conditions and may be an etiological factor as well. The aim of this research is to determine the mechanisms underlying the brain's vulnerability to environmental stress, which lead to chronic fear and anxiety. In particular, we will pursue biochemical and behavioral studies from our laboratories that have established that, in the rat, maternal stress during gestation (prenatal stress) reliably creates offspring which, as adults, 1) exhibit increased fear in a stressful situation, 2) have increased levels of the anxiogenic neuropeptide, corticotropin-releasing factor (CRF), in the amygdala, and 3) have an enlarged amygdala, brought about, at least in part, by an increase in the numbers of neurons and glia. Much evidence has linked the amygdala and CRF to the control of emotional behavior. We hypothesize that the amygdala undergoes structural and neurochemical plasticity in response to stress, and that these changes account for the vulnerability to stress that underlies increased fearfulness. Three specific aims are proposed: 1) to make stereologic measures of amygdaloid volume and cell numbers, autoradiographic measures of CRF receptors, and behavioral measures of hyper-responsiveness to acute stress in normal and prenatally stressed (PS) rats early in development and throughout life, 2) to determine if interventions that will reduce stress during relevant developmental periods will affect normal rats, and ameliorate the accompanying anatomical, biochemical and behavioral changes that occur in PS rats, 3) to determine if the development of hyper-responsiveness to stress in adult rats in response to chronic, daily stressors is accompanied by biochemical and structural reorganization of the amygdala, and 3b) to determine in adult rates if treatment with the anxiolytic drug fluoxetine (Prozac) can block chronic stress- and prenatal stress-induced hyperresponsiveness and changes in amygdaloid volume, cell numbers, and CRF receptors. Determining the differences in the brains of animals that exhibit variations in vulnerability to stress will identify neurobiological mechanisms that lead to anxiety disorders, depression, and drug abuse, and provide new directions for the diagnosis and treatment of stress-related diseases and mental illness.